Carbohydrate antigens are the most abundantly expressed antigens on the cell surface of most cancers and several have been shown to function as effective targets for active and passive specific immunotherapy in clinical trials. Previous studies of biopsy specimens have shown that most breast Cancers express at the cell surface the Thomsen-Friedenreich (TF), sialyl Tn (sTn), Lewis- (Le) and Globo H carbohydrate antigens, and the peptide antigen MUCI. Conjugate Vaccines have proven the most effective approach to augmenting the antibody response against carbohydrate and peptide antigens in our experience. Keyhole limpet hemocyanin (KLH) has been the most potent carrier molecule and the saponin fraction QS-2l the most potent immunological adjuvant. We have completed accrual to a pilot trial with a MUCl-KLH plus QS21 vaccine in patients with breast cancer and recently initiated a pilot trial with an sTn(c )-KLH vaccine in this same patient population. The sTn(c) trial is based on our recent observation that the antigen recognized by monoclonal antibody B72.3 is sTn expressed in a cluster conformation [sTn(c)]. TF, Le and Globo H antigens have been synthesized, conjugated to KLH, and relevant immunogenicity has been confirmed in the mouse. In this proposal, we seek to test the immunogenicity of these single antigen vaccines in Phase I/II studies in breast cancer patients, to construct a consistently immunogenic polyvalent vaccine, and to test this for immunogenicity and toxicity. A large multicenter randomized Phase III clinical trial will be initiated in the second half of year three in patients with Stage 2 or 3 breast Cancer who are free of detectable disease after adjuvant chemotherapy but are at high risk of developing recurrent disease.